Senile dementia, also known as Alzheimer's disease (AD), is a progressive and degenerative neuropathy with clinical and pathological features. Its clinical manifestations mainly are memory (particularly immediate memory) loss, low cognition, retarded thinking, dysfunctional stereogenosis, among others. And its pathological manifestations are the extracellular deposition of amyloid-β (Aβ) which aggregate with other molecules, neurons and non-neural cells to form senile plaques and intracellular neurofibrillary tangles (NFT). In China, the morbidity of AD is in the range of 0.2%-5.98% and increases with the age. It mainly occurs in people above 60-year-old. More than 3.6 millions of people are estimated to be suffering from AD now in China. In a dementia survey in Beijing, it is discovered that the morbidity of vascular dementia is higher than that of AD (Mingyuan Zhang et al., the morbidities of dementia and Alzheimer's Disease. Chinese Journal of Psychiatry 1998; 31(4):195-196). As China is becoming an aged society, the number of dementia patients increases over time. In addition, the morbidity of cerebrovascular diseases is high in old people. The incidence of dementia after apoplexia is estimated to be approximately 9-30.8%. Chronic poor blood supply to brain is another important cause for vascular dementia. In summary, dementia is harmful to patients and loads huge burden to families and the society. Accordingly, it is of great importance to search for an effective medicine to delay and control the development of AD and VD.
Alzheimer's Disease (AD) is the most common cause for the progressive decrease of cognition in old people. Pathological change of AD is mainly presented as the formation of senile plaque with the core of deposited amyloid-β and intracellular neurofibrillary tangles (NFT). Researches have shown that the cholinergic system in the brain was associated with learning and memory functions of human. Cerebral ACh level in AD patients decreases and the activity of choline acetyltransferase, which catalyses the synthesis of ACh, is reduced. The degree of the decrease is closely related with the cognition loss. Furthermore, Oxidative stress and inflammatory reaction are increasingly considered being involved in the pathology of AD. Aβ is composed of 39-43 amino acids, and is the degradation product of amyloid-β precursor (APP). The extent of Aβ deposition is closely associated with neural damages and cognition defects. It is demonstrated in previous studies that continuous i.c.v. perfusion of Aβ (1-40) or Aβ (1-42) would induce damages to the learning and memory of rats (Nitts. et al., β-Amyloid protein-induced Alzheimer's disease animal model. Neurosci. Lett. 1994; 170:63-66), which suggested that memory damage by Aβ aggregation could mimic symptoms of AD patients. L-n-butylphthalide (L-NBP) was shown to have brain-protecting function, for example, the ability to significantly improve mitochondrial function, to improve cerebral microcirculation and energy metabolism, to inhibit neuronal apoptosis, to protect from oxidative damage, to inhibit inflammatory response, to inhibit thrombosis, to reduce intracellular calcium, and to inhibit glutamate release. As such, continuous i.c.v. perfusion of Aβ (1-40) can be used as a model. Morris' water maze and biochemical assays are used to detect the effects of test compounds on short-term memory, stereognosis and oxidative damage in animals.
Vascular dementia (VD) is derived from brain dysfunction induced by cerebrovascular diseases, usually with complications such as multiple infarction of large cerebral arteries, lacunal infarction and brain hypoperfusion. The reduction of cerebral blood flow is associated with the severity of dementia (Roman et al., Vascular dementia: diagnostic criteria for research studies. Neurology 1993; 43:250-260). Chronic progressive poor blood supply to brain causes reduced availability of oxygen, glucose and other essential metabolites, resulting in oxidative damages, impairing mitochondrial functions and biosynthesis in neuronal cells, impeding synaptic transmission, and eventually causing neuropathological changes, i.e. neurodegenerative changes (Beal et al. Do defects in mitochondrial metabolism underlie the pathology of neurodegenerative disease. Trends Neurosci. 1993; 16:125-131). VD patients mainly present progressive loss of short-term memory and stereognosis as well as cognition dysfunction. The occurrence and development of vascular dementia is closely associated with signal transduction of cholinergic neural system, and is also associated with oxidative damage of neural cells. Substantia alba beneath the cortex is pathologically sparse in VD patients. It was shown in extensive investigation that ACh was considered as an important neural transmitter in learning and memory. The cholinergic pathway in AD patients is functionally impaired, with the representation of reduced level of neural transmitter ACh, which is one of the important reasons for the impaired memory and cognition defect (Toghi et al., Cerebrospinal fluid acetylcholine and choline in vascular dementia of Binswanger and multiple small infarct types as compared with Alzheimer-type dementia. J. Neural Transm. 1996; 103:1211-1220). The test compounds can improve ChAT activity, suggesting its ability to increase cholinergic ACh level, which contributes to improve memory function.
During the recent ten years, Morris' water maze has been employed in many studies to test short-term memory and stereotaxic memory of rats, which can sensitively reflect the damages and functional changes of an animal's central neural system (Richard Morris. Developments of a water-maze procedure for studying spatial learning in the rat. J. Neurosci. Methods 1984; 11:47-60), and the effect of test medicines can be observed on this model. Since the main symptom of dementia patients is cognition defect, in particular progressive damage of short-term memory and stereognosis, this is an ideal model for investigating the therapeutic effects of test medicines on presenile dementia (AD) and VD. Continuous hypoperfusion in the rat model of bilateral common carotid artery occlusion may be employed to simulate vascular dementia induced by clinical poor blood supply, and thus can be used to reflect the therapeutic effects of the test medicines on dementia (Ni. J. W. et al. Neuronal damage and decrease of central acetylcholine level following permanent occlusion bilateral common carotid arteries in rats. Brain Res. 1995; 673:290-296).
In 1988, Shuren Yu reported that 3-n-butylphthalide (Ag-1), as a synthetic racemic 3-n-butylphthalide, could be used to improve the impaired learning and memory induced by coriamyrtin in rats and protect hippocampal cells (Shuren Yu, et al. Effect of butylphthalide to improve learning and memory. Chinese Journal of Pharmacology. 1988; 9(5):385-388). Later, celery extract was reported to improve learning and memory in mice of middle and old age (Jing Li, et al. Effect of celery extract on learning and memory in mice of middle and old age. Chinese Traditional and Herbal Drugs 1996; 27(2):104-105; Luosheng Liu, et al. Study on quality standards of ANQINGYIZHI capsule. Journal of Shandong Medical University 2001; 39(6):562-564). But it is not yet reported that an optical stereoisomer, L-n-butylphthalide (L-NBP), can be used to treat senile dementia.